T Cell Therapies Show New Promise in Targeting Solid Tumors

Cell therapies, represented by CAR-T, have demonstrated robust efficacy in treating hematologic malignancies; however, CAR-T therapy has yet to achieve breakthrough progress in the treatment of solid tumors. At this year’s ASCO Annual Meeting, Iovance Biotherapeutics’ innovative therapy based on tumor-infiltrating lymphocytes (TILs) showed superior efficacy in treating solid tumors. This outcome also reminds us that T-cell therapies other than CAR-T may possess unique advantages in the treatment of solid tumors. Recently, the American Association for Cancer Research (AACR) Special Conference on Immune Cell Therapy for Cancer was held in San Francisco, USA. Today, the WuXi AppTec content team will introduce two T-cell therapies that garnered attention at this special conference.

Image source: 123RF

Positive Phase I Clinical Results of Multi-Antigen-Specific T-Cell Therapy for Pancreatic Cancer

Researchers at Baylor College of Medicine have announced the results of a Phase I clinical trial evaluating multiantigen-specific T-cell therapy in patients with pancreatic cancer. Although pancreatic cancer accounts for a relatively small proportion of all cancers, it is known as the “king of cancers” due to its high lethality. Furthermore, the standard of care for most patients currently involves chemotherapy, which is associated with significant toxic side effects, highlighting an urgent need for alternative treatment options.

In this study, scientists isolated T lymphocytes targeting tumor-associated antigens from the blood of pancreatic cancer patients. The targeted antigens included PRAME, SSX2, MAGEA4, NY-ESO-1, and Survivin. After expanding these cells in vitro, the researchers reinfused them into the patients.

In the Phase I clinical trial, a total of 18 patients with pancreatic cancer received this T-cell therapy, among whom 9 patients received first-line treatment combining the T-cell therapy with chemotherapy. Of these 9 patients, 5 achieved disease stabilization or response, including one patient who attained complete response. The duration of response ranged from 6 to 9 months. Among the 6 patients whose disease continued to progress after chemotherapy, this therapy stabilized the disease in 3 patients. No patients experienced systemic toxicity or neurotoxicity related to the T-cell therapy.

“Pancreatic cancer is a very difficult-to-treat cancer. The intensive chemotherapy received by most patients has severe side effects, and there is an urgent need for other treatment options,” said Dr. Brandon G. Smaglo, the lead investigator of this study. “We are pleased that this T-cell therapy for pancreatic cancer demonstrated good tolerability in clinical trials and showed signs of anti-cancer activity. We look forward to treating more patients and continuing to monitor the condition of existing patients.”

Personalized T-Cell Therapy Initiates Phase I Clinical Trial

A limitation of the aforementioned T-cell therapy is the need to isolate and expand patient-derived T cells that target tumor-associated antigens. In some patients, the number of these T cells may be too low to generate a sufficient quantity, or T cell exhaustion may occur during expansion, resulting in inability to proceed with treatment or reduced therapeutic efficacy.

PACT Pharma’s personalized T-cell immunotherapy aims to overcome this limitation. This approach begins with genomic sequencing of the patient’s tumor to identify mutations capable of generating neoantigens. Leveraging this information, the company’s proprietary nanoparticle-based isolation technology is employed to isolate a small subset of patient-derived T cells that already target these neoantigens. Subsequently, researchers identify the DNA sequences encoding the T-cell receptors (TCRs) specific for these neoantigens from the isolated T cells and introduce these sequences into the patient’s own CD8+ T cells using non-viral genome engineering techniques.

▲ Manufacturing process of PACT Pharma’s personalized T-cell therapy targeting neoantigens (Image source: PACT Pharma official website)

This manufacturing process does not require extensive expansion of T cells to generate a large number of T cells targeting neoantigens in the patient’s tumor; upon reinfusion into the patient, these cells can rapidly kill tumors expressing the neoantigens.

At the AACR Special Conference, preclinical trial results were presented in which researchers successfully identified T cells targeting unique neoantigens on tumors from a cancer patient who had responded to PD-1 therapy. Furthermore, T cell therapies generated through genetic engineering based on the TCR sequence information of these T cells demonstrated cancer-specific activity.

Currently, the company has initiated a Phase 1 clinical trial to evaluate the safety and efficacy of this personalized T-cell therapy as a monotherapy or in combination with PD-1 inhibitors in patients with metastatic solid tumors.

Compared with CAR-T cells, T cell therapies expressing TCRs can target intracellular antigens, thereby expanding the range of targets. Meanwhile, directly screening and expanding tumor-targeting T cells obtained from patients avoids the need for genetic engineering of T cells, holding promise to circumvent the complex manufacturing processes and potential side effects associated with genetic modification. We anticipate that these diverse strategies in T cell therapy will soon overcome the challenges in treating solid tumors, bringing innovative treatment options to patients.

References:

[1] Personalized gene-edited immune cell therapy for patients with solid cancers: New data establishes approach for verifying patient-specific cancer mutation targets. Retrieved July 22, 2019, from https://www.prnewswire.com/news-releases/personalized-gene-edited-immune-cell-therapy-for-patients-with-solid-cancers-new-data-establishes-approach-for-verifying-patient-specific-cancer-mutation-targets-300888340.html

[2] Immune cell therapy shows early promise for patients with pancreatic cancer. Retrieved July 22, 2019, from https://medicalxpress.com/news/2019-07-immune-cell-therapy-early-patients.html

[3] AACR Immune Cell Therapies: Early Study Results Suggest Activity of Multiantigen T-Cell Therapy in Patients With Pancreatic Cancer. Retrieved July 22, 2019, from https://ascopost.com/News/60267

Flash Report | Targeting Solid Tumors, T-Cell Therapies Poised for Breakthrough

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